Chemotherapy and radiation therapies are two current clinical modalities commonly used for the treatment of cancer. Mostly these techniques are effective to block the growth of tumor. However, there is often a recurrence of the disease, possibly because of incomplete cell killing or cells acquiring drug resistance. There is also an added disadvantage of non-specific accumulation and killing of normal cells leading to irreparable cytotoxicity in humans. This is mainly because cytotoxic drugs generally do not posses targeting property. The need of the hour is to develop newer drugs which will be targeted to cancers of certain specific origin by utilizing the cancer specific molecular targets, such as, utilizing breast cancer specific proteins, e.g., estrogen receptor, for targeting and killing breast cancer cells.
Estrogen receptor (ER) is a nuclear hormone receptor residing in mostly gynecological cells mainly, breast, uterus, and ovary cells that bear both cancerous and non-cancerous phenotype. The ER is also found to express avidly in vascular endothelial cells wherein it regulates the production of nitric oxide synthases and hence directly help in the positive production and regulation of vascular endothelial growth factors (VEGF) (3). The VEGF is one of the well-known angiogenic factors for the sustained growth of tumor mass.
ER has two subtypes α and β. This receptor, a ligand activated transcription factor upon activation translocates itself into the nucleus. Classically, as a homodimer it binds to specific DNA sequences called Estrogen response elements (ERE) and positively or negatively regulates transcription of target genes. In breast cancer cells ER regulates cancer up-regulating genes such as BCl-2, BRCA-1, and VEGF through ERE-promoter activation of respective genes (1). Therefore, ER is a positive regulator of cancer causing effects and hence ER serves as a very useful target for treating cancer through designing novel ER-targeted therapeutics.
Recently, we have shown that the estrogen the natural ligand to ER, when attached to stealth, cationic liposomal system, mediates anti-cancer gene delivery to breast cancer cells in a target specific manner (2). Estradiol, the endogenous ligand for ER is chemically modified to modulate the ER function which is of high importance for containing variety of diseases including breast cancer and osteoporosis. During the primary stage, i.e., estrogen responsive phase the breast cancer can be successfully contained through chemotherapeutic management. A variety of structural modification and several proactive chemical moieties are included in 17-beta estradiol to develop new generation drugs for the treatment of breast cancer and osteoporosis. There are several examples that can be cited towards this effect: 17α-alkynyl conjugate of estradiol that links between an enediyne system to that of steroidal moiety, possesses comparable ER affinity to estradiol. The compound tentatively acts as anti-cancer, targeted, prodrug through generation of diyl radicals produced by the cycloaromatization of enediyne systems which are known classes of antitumor agents (4). 17-alkylestradiols with alkyl group size is widely varied for their carbon chains from methyl to dodecyl, are also synthesized and tested to find excellent inhibitory effect against steroid sulfatase, the enzyme that is responsible for conversion of sulfated estrogens into free estrogens in normal and cancer cells (5). 17-α azido-alkynyl group containing estradiol is found to possess ER agonistic property (6). C-16 position of estradiol is also utilized for synthesizing ER targeting antagonist/agonists. The C-16 position has been introduced with a carbon chain length and amide bond to induce anti-estrogenic property (7). Synthetic analogues of 2-methoxy estradiol (2-ME2), the endogenous mammalian metabolite of natural hormone estradiol, are also extensively synthesized and studied to find elevated antimitotic activity compared to what is naturally possessed by the metabolite 2-ME2 itself (8-12). An aniline mustard conjugate at 7-α position of estradiol is developed that possess genotoxicity to only ER positive cells through formation of covalent DNA adducts in those cells (13).
The present invention relates to development of a novel series of estrogen receptor binding chemical compounds that contain 17α-estradiol and cationic twin chain lipid moieties. The delivery induced anti-cancer properties of this new class of cationic estradiol described herein is remarkably cell tropic for only gynecological cancer cells, especially, breast cancer cells and also cervical cancer cell. The cellular toxicity of this class of molecules is minimal to null in case of non-gynecological cancer cells and in cells of non-cancerous lineage. This indicates that the cellular toxicity in respective cells is probably mediated through estrogen receptors which are highly implicated in gynecological cancer phenotypes. Thus, the present class of cationic estradiol derivative is likely to find future applications in anticancer therapy for cancers that are implicated with estrogen receptors. Moreover, the present class of compound has cationic moiety in their structure and that the cationic group with optimized length of carbon-chain may have aggregative property as that of cationic liposomes, which may help the molecule to bind with DNA (a poly-anionic biologically important macromolecule). So, the present class of molecule may act as a DNA delivery agent to the cancer cells implicated with ER for the purpose of treating cancers and the references may be made to Carolyn M. Klinge. Nucleic Acid Research, 2001, 29, 2905-2919; Reddy B. S. and Banerjee R. Angewandte Chemie Int. Ed., 2005, 44, 6723-6727; Ken L. Chambliss and Philip W. Shaul, Endocrine Review, 2006, 23, 665-686; Jones et. al. J. Org. Chem., 2001; 66, 3688-3694, and ref. 11 therein; Boivin et. al. J. Med. Chem., 2000, 43, 4465-4478; Kasiotis et. al. Steroids, 2006, 71, 249-255; Pelletier et. al. Steroids, 1994, 59, 536-547; Rao et. al. Steroids, 2002, 67, 1079-1089; Cushman et. al. J. Med. Chem., 1995, 38, 2041-2049; Sachdeva Y. et. al. World Patent No. 9840398, 1998; Purohit A et. al. Int. J. Cancer 2000, 85, 584-589; Brueggemeier R. W. et. al. J. Steroid Biochem Mol Biol 2001, 78, 145-156; Mitra et. al. J. Am. Chem. Soc. 2002, 124, 1862-1863; Jain P T, Seth P, Gewirtz D A Biochim Biophys Acta, 1999, 1451, 224-232; Jain P T, Gewirtz D A, J. Mol. Med., 1998, 76, 709-714.